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Journal of Virology, March 2005, p. 3536-3543, Vol. 79, No. 6
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.6.3536-3543.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Increased Multinucleoside Drug Resistance and Decreased Replicative Capacity of a Human Immunodeficiency Virus Type 1 Variant with an 8-Amino-Acid Insert in the Reverse Transcriptase

Lia van der Hoek,1 Nicole Back,1 Maarten F. Jebbink,1 Anthony de Ronde,1 Margreet Bakker,1 Suzanne Jurriaans,1 Peter Reiss,2 Neil Parkin,3 and Ben Berkhout1*

Department of Human Retrovirology,1 Department of Infectious Diseases, Tropical Medicine and AIDS and National Antiviral Therapy Evaluation Center (NATEC), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands,2 ViroLogic Inc., South San Francisco, California3

Received 20 August 2004/ Accepted 3 November 2004

Resistance to antiretroviral drugs is generally conferred by specific amino acid substitutions, rather than insertions or deletions, in reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1). The exception to these findings is the amino acid insertions found in the ß3-ß4 loop of the RT enzyme in response to treatment with nucleoside reverse transcriptase inhibitors. This insert consists most commonly of two amino acids, but we describe in detail the evolution of a variant with an 8-amino-acid (aa) insert in a patient treated with zidovudine (ZDV) and 2'-3'-dideoxycytidine (ddC). The 24-nucleotide insert is a partial duplication of local sequences but also contains a sequence segment of unknown origin. Extensive sequence analysis of longitudinal patient samples indicated that the HIV-1 population prior to the start of therapy contained not the wild-type amino acid 215T in RT but a mixture with 215D and 215C. Treatment with ZDV and subsequent ZDV-ddC combination therapy resulted in the evolution of an HIV-1 variant with a typical ZDV resistance genotype (41L, 44D, 67N, 69D, 210W, 215Y), which was slowly replaced by the insert-containing variant (41L, 44D, insert at position 69, 70R, 210W, 215Y). The latter variant demonstrated increased resistance to a wide range of drugs, indicating that the 8-aa insert augments nucleoside analogue resistance. The gain in drug resistance of the insert variant came at the expense of a reduction in replication capacity when assayed in the absence of drugs. We compared these data with the resistance and replication properties of 133 insert-containing sequences of different individuals present in the ViroLogic database and found that the size and actual sequence of the insert at position 69 influence the level of resistance to nucleoside analogues.

* Corresponding author. Mailing address: Department of Human Retrovirology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. Phone: 31 20 566 4822. Fax: 31 20 566 6064. E-mail: b.berkhout{at}amc.uva.nl.

Journal of Virology, March 2005, p. 3536-3543, Vol. 79, No. 6
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.6.3536-3543.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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